Publications by authors named "Jinzhu Fan"

8 Publications

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Targeting the CtBP1-FOXM1 transcriptional complex with small molecules to overcome MDR1-mediated chemoresistance in osteosarcoma cancer stem cells.

J Cancer 2021 1;12(2):482-497. Epub 2021 Jan 1.

Department of Orthopaedics, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi, China.

Chemoresistance is a major barrier for the chemotherapy of osteosarcoma. The induction of multidrug resistance protein 1 (MDR1), an ATP-dependent transporter, can efflux anti-cancer drugs, thereby decreasing chemosensitivity. However, an actual involvement of MDR1 in the chemoresistance of osteosarcoma cells has not been established. We obtained two cisplatin (CDDP)-resistant osteosarcoma cancer stem cell (CSC) lines using sphere formation medium supplemented with CDDP. These two CDDP-resistant CSC cell lines showed substantial cell proliferation, colony formation, cell invasion, and tumor growth in the presence of CDDP. Microarray analysis revealed that three genes, , (forkhead box M1), and (C-Terminal binding protein 1), showed significant overexpression in both cell lines. Mechanistically, CtBP1 assembled with FOXM1 to form a transcriptional complex, which docked onto the promoter to activate expression. Knockdown or inhibition of the CtBP1-FOXM1 components with specific small molecules, including NSM00158 and NSC95397 for CtBP1 and RCM1 for FOXM1, significantly repressed expression. Administration of these three small molecules also significantly inhibited tumor growth in mouse tumor xenograft model. The MDR1-mediated chemoresistance could be reversed by NSM00158 and RCM1. Collectively, our data revealed that the CtBP1-FOXM1 complex activated expression and that targeting this complex with their specific inhibitors could reverse MDR1-mediated chemoresistance both and . Our results indicate a new therapeutic strategy for overcoming chemoresistance during osteosarcoma treatment.
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http://dx.doi.org/10.7150/jca.50255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739006PMC
January 2021

Orai1 Promotes Osteosarcoma Metastasis by Activating the Ras-Rac1-WAVE2 Signaling Pathway.

Med Sci Monit 2019 Dec 4;25:9227-9236. Epub 2019 Dec 4.

Department of Spinal Surgery, Hong Hui Hospital, Xi'an Jiao Tong University, Xi'an, Shaanxi, China (mainland).

BACKGROUND The purpose of this study was to investigate whether Orai1 plays a role in the metastasis of osteosarcoma. MATERIAL AND METHODS The expression of Orai1 was silenced by small interfering RNAs against Orai1 (Orai1 siRNA) in osteosarcoma MG-63 cells. Various experiments were carried out to detect the changes in migration, invasion, and adhesion ability of these osteosarcoma cells. Furthermore, the activity of Rac1, Wave2, and Ras was detected using Western blot analysis. Moreover, the Rac1 and Ras inhibitors were used to confirm whether the Ras-Rac1-WAVE2 signaling pathway was involved in osteosarcoma metastasis promoted by Orai1. RESULTS We found that the migration, invasion, and adhesion ability of MG-63 cells were significantly reduced after silencing Orai1 expression (p<0.05). Moreover, the activity of the Rac1-WAVE2 signaling pathway was significantly inhibited after silencing of Orai1 expression (p<0.05). After the Rac1 inhibitor was added, Orai1 siRNA could not further inhibit migration, invasion, and adhesion of the osteosarcoma cells. Further experiments showed that Ras activity was significantly inhibited after silencing Orai1 expression (p<0.05). Moreover, Orai1 siRNA did not further inhibit the activity of the Rac1-WAVE2 signaling pathway nor did it further inhibit the migration, invasion, and adhesion ability of osteosarcoma cells following the addition of Ras inhibitors. CONCLUSIONS Orai1 activates the Ras-Rac1-WAVE2 signaling pathway to promote metastasis of osteosarcoma. Abnormal expression or function of Orai1 may be an important cause of osteosarcoma metastasis.
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http://dx.doi.org/10.12659/MSM.919594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909920PMC
December 2019

Downregulation of Bach1 protects osteoblasts against hydrogen peroxide-induced oxidative damage in vitro by enhancing the activation of Nrf2/ARE signaling.

Chem Biol Interact 2019 Aug 11;309:108706. Epub 2019 Jun 11.

Department of Bone Reconstructive Microsurgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.

Oxidative-stress-induced osteoblast dysfunction plays an important role in the development and progression of osteoporosis. BTB and CNC homology 1 (Bach1) has been suggested as a critical regulator of oxidative stress; however, whether Bach1 plays a role in regulating oxidative-stress-induced osteoblast dysfunction remains unknown. Thus, we investigated the potential role and mechanism of Bach1 in regulating oxidative-stress-induced osteoblast dysfunction. Osteoblasts were treated with hydrogen peroxide (HO) to mimic a pathological environment for osteoporosis in vitro. HO exposure induced Bach1 expression in osteoblasts. Functional experiments demonstrated that Bach1 silencing improved cell viability and reduced cell apoptosis and reactive oxygen species (ROS) production in HO-treated cells, while Bach1 overexpression produced the opposite effects. Notably, Bach1 inhibition upregulated alkaline phosphatase activity and osteoblast mineralization. Mechanism research revealed that Bach1 inhibition increased the activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling and upregulated heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1 mRNA expression. The Bach1 inhibition-mediated protective effect was partially reversed by silencing Nrf2 in HO-exposed osteoblasts. Taken together, these results demonstrate that Bach1 inhibition alleviates oxidative-stress-induced osteoblast apoptosis and dysfunction by enhancing Nrf2/ARE signaling activation, findings that suggest a critical role for the Bach1/Nrf2/ARE regulation axis in osteoporosis progression. Our study suggests that Bach1 may serve as a potential therapeutic target for treating osteoporosis.
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http://dx.doi.org/10.1016/j.cbi.2019.06.019DOI Listing
August 2019

MicroRNA-499a-5p inhibits osteosarcoma cell proliferation and differentiation by targeting protein phosphatase 1D through protein kinase B/glycogen synthase kinase 3β signaling.

Oncol Lett 2018 Apr 17;15(4):4113-4120. Epub 2018 Jan 17.

Department of Orthopedics, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710054, P.R. China.

A number of studies have attempted to elucidate the association between mircoRNAs (miRNAs/miRs) and cancer-associated processes. The aim of the present study was to determine how miR-499a-5p intervenes in human osteosarcoma cell proliferation and differentiation. The cancerous tissues and adjacent non-cancerous tissues of 62 patients with osteosarcoma (OS) were collected. miRNA microarray analysis revealed that 29 miRNAs were upregulated while 26 were downregulated, among which miR-499a-5p expression was the most decreased. Western blot analysis and reverse transcription-quantitative polymerase chain reaction demonstrated that the mRNA and protein expression of miR-499a-5p was lower, while that of protein phosphatase 1D () was higher in OS tissues compared with expression levels in normal tissues. Furthermore, miR-499a-5p expression was markedly decreased in the metastatic tumors and in those at stage III+IV compared with the non-metastatic tumors and those at stage I, respectively. In addition, following transfection of the human OS MG-63 cell line with an miR-499a-5p mimic, the expression of miR-499a-5p was elevated while the protein and mRNA expression of was decreased. When combining these findings with the information obtained from the Targetscan predictive software, it was confirmed that was targeted by miR-499a-5p. In MG-63 cells transfected with an miR-499a-5p mimic, -associated downstream proteins phosphorylated protein kinase B (p-Akt) and phosphorylated glycogen synthase kinase 3β (p-GSK-3β) were significantly downregulated compared with the negative control (NC) group, while the expression of p-Akt and p-GSK-3β were significantly elevated in the tumor tissues compared with the adjacent non-tumor tissues. Simultaneously, the growth and proliferation activity of MG-63 cells were notably reduced when transfected with the miR-499a-5p mimic, compared with the NC group. Therefore, it may be concluded that miR-499a-5p suppresses OS cell proliferation and differentiation by targeting through modulation of Akt/GSK-3β signaling.
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http://dx.doi.org/10.3892/ol.2018.7814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844143PMC
April 2018

Blockade of Interleukin 6 by Rat Anti-mouse Interleukin 6 Receptor Antibody Promotes Fracture Healing.

Biochemistry (Mosc) 2017 Oct;82(10):1193-1199

Southern Medical University, Nanfang Hospital, Department of Burn, Guangzhou, Guangdong, 510515, China.

Level of interleukin 6 (IL-6) is associated with fracture healing. This study was performed to explore the effect of IL-6 blockade on fracture healing. Clinical serum levels of IL-6 and tumor necrosis factor-α (TNF-α) were evaluated by enzyme-linked immunosorbent assay (ELISA). For animal experiments, the IL-6 levels after fracture and treatment with rat anti-mouse IL-6 receptor antibody (MR16-1) were assessed. Then, mice were assigned into four or seven groups: control group, fracture group, isotype IgG group, and MR16-1 groups. Serum levels of IL-6 and TNF-α, relative flexural rigidity, and mRNA levels of osteoblast-specific genes were respectively assayed by ELISA, three-point bending test, and quantitative reverse transcription PCR (qRT-PCR). Serum levels of IL-6 and TNF-α after fracture in humans and mice were increased. The increase in IL-6 and TNF-α levels in murine serum was attenuated by MR16-1 treatment. The three-point bending test showed the relative flexural rigidity of the femur was decreased after fracture, whereas the decrease was alleviated by MR16-1 treatment. The qRT-PCR results demonstrated mRNA levels of osteoblast-specific genes were upregulated after fracture and then further upregulated by MR16-1 treatment in a dose-dependent manner. Collectively, the serum level of IL-6 was elevated after fracture both in clinical and murine samples. IL-6 blockade by MR16-1 promoted fracture healing, which might be associated with changes in expression of osteoblast-specific genes.
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http://dx.doi.org/10.1134/S0006297917100121DOI Listing
October 2017

Ginsenoside Rb2 inhibits osteoclast differentiation through nuclear factor-kappaB and signal transducer and activator of transcription protein 3 signaling pathway.

Biomed Pharmacother 2017 Aug 8;92:927-934. Epub 2017 Jun 8.

Department of Orthopaedics, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, China.

Ginsenoside-Rb2 (Rb2) is a 20(S)-protopanaxadiol glycoside extracted from ginseng possessing various bioactivities which has drawn considerable interest regarding the area of bone metabolism. However, the effect of Rb2 on osteoclast differentiation remains unknown. In this study, we aimed to investigate the potential role of Rb2 in regulating osteoclast differentiation and the underlying molecular mechanisms. Osteoclast differentiation was induced by receptor activator nuclear factor-kappaB (NF-κB) ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in mouse RAW 264.7 cells. The results showed that Rb2 dose-dependently inhibited the formation of the tartrate resistant acid phosphatase (TRAP)-positive multinucleated cells and TRAP expression. Furthermore, Rb2 promoted osteoprotegerin expression and bone resorption. The expression of osteoclast marker genes including nuclear factor of activated T cells c1 (NFATc1), c-Fos, OSCAR, and cathepsin K were also markedly inhibited by Rb2 treatment. Moreover, Rb2 significantly inhibited the RANKL-induced NF-κB activation. In addition, Rb2 also markedly suppressed the activation of signal transducer and activator of transcription protein 3 (STAT3) signaling pathway. Interestingly, the knockdown of STAT3 significantly strengthened the inhibitory effect of Rb2 on osteoclast differentiation. Taken together, our study suggests that Rb2 inhibits osteoclast differentiation associated with blocking NF-κB and STAT3 signaling pathways.
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http://dx.doi.org/10.1016/j.biopha.2017.05.115DOI Listing
August 2017

MicroRNA-34c promotes osteoclast differentiation through targeting LGR4.

Gene 2017 Apr 24;610:1-8. Epub 2017 Jan 24.

Department of Orthopaedics, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China.

MicroRNAs have emerged as important regulators of osteoclast differentiation in recent years. Of these, miR-34c has been reported to play an important role in bone development. However, its role and the underlying mechanism in osteoclast differentiation remains poorly understood. In this study, we aimed to investigate the precise role and molecular mechanism of miR-34c in osteoclast differentiation. We found an obvious increase in miR-34c expression during osteoclast differentiation in osteoclast precursors induced by receptor activator of nuclear factor κB (NF-κB) ligand and macrophage colony-stimulating factor in vitro. Further experiments showed that overexpression of miR-34c significantly promoted osteoclast differentiation while suppression of miR-34c showed the opposite effect. Interestingly, bioinformatics analysis and dual-luciferase reporter assays showed that miR-34c targets the 3'-untranslated region of leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4). The expression of LGR4 was regulated by miR-34c in osteoclasts. Moreover, miR-34c regulated NF-κB and glycogen synthase kinase 3-β signaling during osteoclast differentiation. Overexpression of LGR4 partially reversed the promoting effect of miR-34c overexpression on osteoclast differentiation. Taken together, our study suggests that miR-34c contributes to osteoclast differentiation by targeting LGR4, providing novel insights into understanding the molecular mechanism underlying osteoclast differentiation.
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http://dx.doi.org/10.1016/j.gene.2017.01.028DOI Listing
April 2017

Approach to osteomyelitis treatment with antibiotic loaded PMMA.

Microb Pathog 2017 Jan 26;102:42-44. Epub 2016 Nov 26.

Department of Orthopedics, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi 710054, China.

Background: To reduce the incidence of osteomyelitis infection, local antibiotic impregnated delivery systems are commonly used as a promising and effective approach to deliver high antibiotic concentrations at the infection site.

Objective: The objective of this review was to provide a literature review regarding approach to osteomyelitis treatment with antibiotic loaded PMMA.

Study Design: Literature study regarding osteomyelitis treatment with antibiotic loaded carriers using key terms Antibiotic, osteomyelitis, biodegradable PMMA through published articles. Hands searching of bibliographies of identified articles were also undertaken.

Conclusion: We concluded that Antibiotic-impregnated PMMA beads are useful options for the treatment of osteomyelitis for prolonged drug therapy.
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http://dx.doi.org/10.1016/j.micpath.2016.11.016DOI Listing
January 2017
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